Targeting tumor vessels is proving to be an effective approach in cancer therapy. In addition to the administration of anti-angiogenic drugs, a complementary strategy is to use vascular disrupting agents to damage tumor endothelial cells, which directly shuts down tumor vascular perfusion. Our preliminary studies show that the stilbene derivative, Stilbene 5c, can effectively suppress tumor vascular perfusion without compromising normal organ perfusion. However, stilbene used as a single agent has only marginal therapeutic efficacy in xenograft models. We propose to investigate the mechanism(s) of tumor vascular suppression and compensatory tumor mechanisms that occur after stilbene treatment. Specific aim 1 is to study how stilbene suppresses tumor blood flow. Various imaging modalities, including high frequency ultrasound, luciferase imaging, and the use of oxygen blood flow sensors as well as assessment of tumor vascular density will be used to investigate tumor blood flow after stilbene treatment. Specific aim 2 will investigate the rebound phenomenon observed in our preliminary studies. In particular, the work will focus on the contribution of nitric oxide-induced vasodilatation. Specific aim 3 will investigate the roles of HIF-a and VEGF on the effectiveness of stilbene 5c. We will quantify the levels of circulating endothelial progenitor cells and use small interfering RNA to down-regulate HIF-a and VEGF to assess their involvement in mobilization of endothelial progenitor cells and influence on therapeutic efficacy of stilbene 5c. Successful completion of this study will serve to elucidate the mechanisms of action and compensatory responses to a new class of vascular disrupting agents with the goal of facilitating their future clinical application.